The application's broad, long-term objectives are to discover a blood test for early detection of ovarian cancer that will reduce ovarian cancer mortality through regular testing of targeted populations. Initially these populations would include women at high risk due to family history and/or presence of a BRCA1 or BRCA2 mutation within the family, and all postmenopausal women. This is the age group where the incidence of disease is highest. The test requires high sensitivity for early stage disease and very high specificity so that few false positive tests will occur for each true positive test. The specific aims are 1) to discover high probability candidate biomarkers through longitudinal proteomic analysis of serial plasma obtained from screening studies of large cohorts, 3) prioritize candidate protein biomarkers for verification by change-point analysis and ranking by earliest change-point, 4) construct targeted mass spectrometric assays for the top 50 protein candidates and measure these candidates in longitudinal plasma in cases prior to clinical detection and in controls, where cases and controls are from an ovarian cancer screening trial, 4) determine which candidates have earliest sensitivity by estimating the change-point at which the candidate rises significantly above baseline, and 5) discover high probability candidate DNA mutational biomarkers from genomic analysis of cervico-vaginal fluid in women with malignant and benign pelvic masses, 6) validate DNA mutational candidates in an independent validation sample set of CVF from cases and benign controls. Further refinement and testing of proteomic and genomic biomarkers and their combination to identify the best panel and classifier of early detection ovarian cancer biomarkers in the biorepositories of larger scale screening studies is planned but is outside the scope of this application.